Water soluble steroids



Unite WATER SOLUBLE STEROIDS Gerald D. Laubach, Jackson Heights, N. Y., assignor to Chas. Pfizer & Co., Inc., New York, N. Y., a corporation of Delaware No Drawing. Application May 16, 1955 Serial No. 508,803

3 Claims. (Cl. 167-52) This formula includes both compounds of the pregnane series and also compounds of the allopregnane series. In this formula E is used to denote an ionic ester group as that group is defined in the parent application.

In the above mentioned parent application, there were described and claimed compounds having the general formula in which E is selected from the group consisting of ionic ester groups having the formula ooL-c0M+ and ionic ester groups having the formula 0fiL-NR3+z wherein L is chosen from the group consisting of 2)n 2)1t and 2)1., n being a number from 1 to 6, M+ is a cation selected from the class consisting of Na+, 14+ and NRJ, each R represents a member of the group consisting of hydrogen and alkyl, hydroxyalkyl, hydrocarbon carboxyalkyl, aminoalkyl, aryl and aralkyl groups, each containing up to States atent ten carbon atoms, and Z- is a pharmacologically accept able anion. D in this formula may be keto.

The compounds of the present invention are prepare by methods similar to those used in preparing the com pounds in the parent application. It will be observe that the parent application describes compounds contain ing a keto group at the 3-position. The present com pounds are prepared by removal of this 3-keto group To accomplish this removal, 2l-hydroxypregnane-3, 2C dione or 2l-hydroxyallopregnane-B, 20-dione with an ac} group present at the 2l-position is converted to a 3-thic ketal. This is accomplished by reaction with, for example ethane dithiol and an acid catalyst as described in co pending application Serial No. 508,802, filed May It 1955, now abandoned, by Gerald D. Laubach. The thic ketal is then treated with Raney nickel in an amoun which may range from a stoichiometric equivalent to ten-fold excess. The temperature used for this reactio: may vary anywhere from 20-100 C. and the time re quired will vary from 1 to 12 hours. An inert organi solvent, for example, alcohol or dioxane, or mixture thereof, is employed. This treatment with Raney nickc removes the thioketal group and results in the formatio: of a completely hydrogenated 3-position.

The acyl group which has been present during th above reactions is then removed by hydrolysis, for ex ample with potassium carbonate in methanol thereb producing the free 21-position alcohol which is then con verted to an ionic ester at the 21-position as described i the parent application. If it is desired to prepare ioni ester groups which are succinates, the succinate group may be used as the original acylating group and carriet through the above synthesis.

The novel compounds of this present invention hav properties which make them very valuable. Each ha the three characteristics of being water soluble, hormor ally inactive and active as a central nervous system de pressant. They are useful as anesthetic, anti-convulsan: sedative, analgesic and hypnotic agents. They may b employed alone or in combination with other centre nervous system depressants. Their water solubility i such that they may be administered intravenously in ster ile aqueous solution. Filtration through a Seitz filter i a convenient method of sterilizing a solution to be in jected. The compounds may also be employed in aque ous solutions containing other solutes, for example enough saline or glucose to make them isotonic. The are also suitable for administration by other routes, fo example, orally, subcutaneously, and intramuscularh The compounds may be combined with a variety of pha1 macologically acceptable carriers, the choice of whic' will depend upon the desired method of administratio and be determined by standard pharmaceutical practice: for example, the compounds may be administered orall in the form of tablets containing an excipient such a starch, or as an elixir or suspension in a carrier.

The following examples are given solely for the pin pose of illustration and are not to be construed as tations of this invention, many variations of which ar possible without departing from the spirit or scope thereo:

Example 1 Two grams of 21-hydroxypregnane-3, 20-dione sodiur hemisuccinate was added to an equivalent amount of etl ane dithiol. The mixture was cooled below 0 C. wit an ice salt mixture. A current of gaseous hydroge chloride was passed through for three minutes and th mixture was then stirred in a refrigerator for 14 hour: The excess ethane dithiol was removed in a vacuum desic cator in the presence of sodium hydroxide. The soli product, the 3-ethylene thioketal of 2l-hydroxypregnanc 3, ZO-dione hemisuccinate was recovered.

Bytheuse. of procedures analogous to the above, iden- :alresults are obtained when allo compounds are used, see -the.configuration at the -position has noinfiuence l the course of'these reactions. Identical results were so obtained when the. 2l-positionwas protected with heracyl groups, for.example, the acetate or benzoate. l these latter'cases, however, it was necessary to remove .e protecting acyl group before, proceeding to introduce .e. ionic ester group. This removal of the acyl group asreadily' accomplished :by treatment with, alcoholic a tassium carbonate.

Whatis claimed is:

1. A compound having the formula E be, i 0 CH3 in which E is selected from the group consisting of ionic ester groups having the formula and ionic ester groups having the formula -O("3LNRa Z- wherein L is chosen from, the group consisting of."

2)n 2)1L- and z)n; n being a number from 1 to 6, M+ is a cation selected from the class consisting of Na+, K+ and NRpE, each R represents a member of the group consisting of hydrogen and alkyl, hydroxyalkyl, hydrocarbon carboxyalkyl, ami- V noalkyl, aryl and aralkyl groups, each containing up to ten carbon atoms, and Z- is a pharmacologically acceptable anion.

2. A pharmaceutical composition which comprises a compound as claimed in claim 1 together. with aphar maceutically acceptable carrier.

3. An anesthetic agent comprising a.sterile,.injectable aqueous solution of a compound, asr'claimed in claim: 1.

No referencescited; 

1. A COMPOUND HAVING THE FORMULA 